Albright hereditary osteodystrophy is an autosomal dominant disorder characterized by short stature, obesity, subcutaneous ossifications and brachydactyly. Some family members have these features in association with resistance to multiple hormones which activate Gs-coupled receptors (pseudohypoparathyroidism type Ia, PHP Ia) while others present with the somatic features alone (pseudopseudohypoparathyroidism, PPHP). Peripheral tissues from most affected patients have a 50% deficiency in Gs-alpha subunit function and/or expression in peripheral tissues (both PHP Ia and PPHP). We have identified a number of heterozygous inactivating mutations of the Gs-alpha gene in affected patients (both PHP Ia and PPHP). Three missense mutations, serine 250 to arginine, arginine 258 to tryptophan and deletion of asparagine 99 have been identified in AHO patients. Functional characterization and molecular modeling suggest that serine 250 interacts with residues of the guanine nucleotide binding pocket. The arginine 258 mutation leads to abnormal receptor-mediated activation. It has been proposed that tissue-specific imprinting of the Gs-alpha gene may explain the observation that maternal transmission of the Gs defect leads to offspring with PHP Ia while paternal transmission leads to PPHP. In order to study this question further, Gs-alpha 'knockout' (GsKO) mice were generated using standard gene knockout methods. Homozygous GsKO (-/-) is embryonic lethal. Heterozygotes (+/-) have distinct phenotypes depending on the parental inheritance. These phenotypes are similar to those previously described for uniparental disomies of the distal chromosome 2 imprinted region to which the gene maps. Maternal, but not paternal. transmission of GsKO, leads to parathyroid hormone (PTH) resistance (as in humans). Paternal transmission of GsKO leads to markedly decreased white fat accumulation while maternal transmission leads to obesity. Immunoblots are consistent with tissue-specific imprinting of the gene (in adipocytes and renal cortex but not in renal inner medulla) with the paternal allele normally silent.